Networks of blood proteins in the neuroimmunology of schizophrenia

Abstract

Levels of certain circulating cytokines and related immune system molecules are consistently altered in schizophrenia and related disorders. In addition to absolute analyte levels, we sought analytes in correlation networks that could be prognostic. We analyzed baseline blood plasma samples with a Luminex platform from 72 subjects meeting criteria for a psychosis clinical high-risk syndrome; 32 subjects converted to a diagnosis of psychotic disorder within two years while 40 other subjects did not. Another comparison group included 35 unaffected subjects. Assays of 141 analytes passed early quality control. We then used an unweighted co-expression network analysis to identify highly correlated modules in each group. Overall, there was a striking loss of network complexity going from unaffected subjects to nonconverters and thence to converters (applying standard, graph-theoretic metrics). Graph differences were largely driven by proteins regulating tissue remodeling (e.g. blood-brain barrier). In more detail, certain sets of antithetical proteins were highly correlated in unaffected subjects (e.g. SERPINE1 vs MMP9), as expected in homeostasis. However, for particular protein pairs this trend was reversed in converters (e.g. SERPINE1 vs TIMP1, being synthetical inhibitors of remodeling of extracellular matrix and vasculature). Thus, some correlation signals strongly predict impending conversion to a psychotic disorder and directly suggest pharmaceutical targets.

A Meta-analysis of Immune Parameters, Variability, and Assessment of Modal Distribution in Psychosis and Test of the Immune Subgroup Hypothesis

“…Indeed, Weickert and colleagues have employed cluster analysis to divide patients with schizophrenia-spectrum disorders into subgroups based on elevation of multiple cytokines in unison. 27,29 They have observed that, compared with controls, a greater proportion of patients clustered within an “elevated cytokine subgroup.” Jeffries and colleagues 107 have used graph theory to examine network connectivity of blood proteins related to neuroimmunology across the psychosis spectrum, observing that protein correlation networks can successfully differentiate between controls, and prodromal individuals who transition/do not transition to psychosis. Based on the current meta-analysis, we are unable to comment on whether there is a FEP immune subgroup characterized by an abnormal immune parameter network.…”

MMPs in learning and memory and neuropsychiatric disorders

“…Rahimi et al [230] showed that there were no significant differences in the individual levels of MMP-9 and TIMP-1 genes in schizophrenia patients, but the MMP-9/TIMP-1 ratio was significantly altered (see also Ref. [231]). Similarly, upregulated MMP-9 serum levels were found to be strongly associated with levels of mature BDNF (MMP-9 aids in the formation of mature BDNF from pro-BDNF) in schizophrenia patients [232].…”

Integrated Lipidomics and Proteomics Point to Early Blood-Based Changes in Childhood Preceding Later Development of Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children

“…Furthermore, the present findings are broadly in line with our findings from the previous discovery metabolomics, lipidomic, and proteomic study in the ALSPAC cohort, in which we demonstrated similar changes at 12 years of age for subjects who later went on to develop PD (22) . The findings have the potential to contribute to risk calculators for future psychotic illness and mental disorders 4 , 56 , 57 as well as to an increased understanding of psychosis and psychiatric illness as a multisystem disorder involving lipids and proteins 22 , 23 , 29 . Critically, a novelty of our study lies in the integration of proteomic and lipidomic data, specifically of the PCs and LPCs and the protein members of the complement and coagulation cascades from the same subjects.…”

“…Both the coagulation and the complement pathways have recently been highlighted in schizophrenia 57 , 73 , 74 . Our current study used the semitargeted proteomic method of DIA to extend these findings and show that upregulation of PLG within the coagulation pathway at 12 years of age is associated with later PEs.…”